Over what albumin concentration range are adjusted calcium equations valid?

Calcium is the fifth most abundant element in the organism. This essential element is primarily available to the body through dietary intake. In the body, the vast majority of calcium (>99%) is stored in bones, and thus plays a major role in bone mineralization. In plasma, calcium (<1% of the body’s calcium) is found either in free ionized form or bound (mainly to albumin), but only ionized calcium (Ica) is active and plays a major role, especially in intra- and extracellular signalling pathways, in nerve impulse transmission and muscle contraction (1). Thus, calcium is involved in numerous physiological functions, and is therefore commonly measured in clinical practice. Indeed, dyscalcemia can lead to serious clinical consequences. In clinical practice, the total calcium (Tca) is mostly measure, representing both free and bound calcium. To estimate the active form by Tca, corrected calcium (Cca) could be determined. Hence, many adjusted calcium equations have been developed using albumin levels such as Payne, the most used in practice, Clase or Jain formulas, etc. (2-4). However, the literature suggests some limits about this adjustment, regardless of albumin levels.

Indeed, Ladenson et al. (5) compared different adjusted calcium equations in a population of 375 hospitalized patients and 53 controls. In this study, Tca and Ica were measured, and Cca was calculated according to 13 formulas. The aim was to evaluate the effectiveness of the calcium correction formulas. Finally, this study showed that Cca does not significantly improve calcium true state (determined by Ica) than Tca, which means that uncorrected calcium would sometimes give a better indication of calcium status than Cca (5). Moreover, Dickerson et al. (6) evaluated adjusted calcium equations from literature (22 formulas). They showed that seven formulas estimated Ica and 15 estimated corrected Tca. On 100 patients admitted to the trauma intensive care unit who were referred to the Nutrition Support Service, they showed a low sensitivity of these formulas for both hypocalcemia and hypercalcemia (25% and 15% respectively) (6). Additionally, Mateu-de Antonio (7) evaluated 11 formulas in two cohorts of 269 and 146 hospitalized patients, showing a poor predictive value for hypocalcemia (26% for Payne formula).

Recently, a retrospective study performed by Pekar et al. (8) on 5,055 patients found that Cca tends to overestimate calcium status, and more particularly in case of low albumin levels or blood pH disorders. In this study, for the patients with normal levels of albumin, the global agreement rate for the Cca was between 64% and 65% according to the formulas (between 63% and 66% for Tca) suggesting no significant improvement of Cca compared to Tca (8). Also, a study performed by Smith et al. (9) retrospectively on 5,553 patients and prospectively on 440 patients concludes that the Cca tends to overestimate calcium, with a more pronounced effect in patients with low albumin or renal impairment. Hence, these last two studies show that the correction formulas are even more inefficient in case of hypoalbuminemia.

Overall, numerous factors influence the binding of calcium to albumin, and the pH seems to be a major determinant, explaining why adjusted calcium equations have some limitations. Moreover, adjusted equations suppose a constant link between albumin and calcium, regardless of albumin level. However, in case of hypoalbumin state, the calcium affinity for albumin increase (10). Thus, the use of Cca can lead to patients’ mismanagement. The formulas to correct Tca using pH would be of limited interest. Indeed, the measure of pH determination and Ica measurement require same strict pre-analytical conditions and can be performed under the same blood-gas analyzers (11). Ideally, measurement of Ica should be preferred in whole blood collected anaerobically into blood gas syringes, to determine the calcium status of patients.

Because Ica is not yet measured routinely, a formula to predict hypocalcemia using the anion gap (AG) has been proposed by Yap et al. (12). Authors evaluated their formula on a set of patients from intensive care unit, Ica measurement had been performed simultaneously with Tca measurement, either by venous blood gas (VBG cohort) or by arterial blood gas (ABG cohort); 182 patients with hypocalcemia (Ica <1.1 mmol/L) were selected: 96 in the VBG cohort and 86 in the ABG cohort. To estimate Ica from Tca, 2 correction formulas were evaluated, using, in addition to the albumin level, the AG or its components (sodium, chloride, total carbon dioxide). The Cca was also calculated (correction only by albumin level). Finally, the correction with AG or its components were better than Cca, indeed albumin correction does not involve important variation of the complexed fraction of Tca. The inverse correlation between AG and Ica suggests that AG might be a good indicator of the complexed fraction (12).

To conclude, albumin-adjusted calcium equations should no longer be used routinely, regardless of albumin level. Moreover, if calcium affinity to albumin is dependent on the pH, the use of pH adjusted calcium equations would be of limited interest because all blood gas analyzers can directly measure Ica. Ica assay is to be preferred and should be used routinely: representing the active form of calcium, Ica it is the best reflection of calcium status. Hence, it allows to avoid misclassifications of patients. Calcium correction equations lead to higher discordance rate than Tca uncorrected, we also suggest to use Tca in situations in which the measurement of the Ica is impossible, especially when it is impossible to collect a blood gas. New formulas are under development, considering the AG or its components, but are not yet used routinely.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Nuthar Jassam) for the series “Calcium Adjustment in Laboratory Medicine” published in Journal of Laboratory and Precision Medicine. The article has undergone external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-22-33/coif). The series “Calcium Adjustment in Laboratory Medicine” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Peacock M. Calcium metabolism in health and disease. Clin J Am Soc Nephrol 2010;5:S23-30. [Crossref] [PubMed]
2. Payne RB, Little AJ, Williams RB, et al. Interpretation of serum calcium in patients with abnormal serum proteins. Br Med J 1973;4:643-6. [Crossref] [PubMed]
3. Jain A, Bhayana S, Vlasschaert M, et al. A formula to predict corrected calcium in haemodialysis patients. Nephrol Dial Transplant 2008;23:2884-8. [Crossref] [PubMed]
4. Clase CM, Norman GL, Beecroft ML, et al. Albumin-corrected calcium and ionized calcium in stable haemodialysis patients. Nephrol Dial Transplant 2000;15:1841-6. [Crossref] [PubMed]
5. Ladenson JH, Lewis JW, Boyd JC. Failure of total calcium corrected for protein, albumin, and pH to correctly assess free calcium status. J Clin Endocrinol Metab 1978;46:986-93. [Crossref] [PubMed]
6. Dickerson RN, Alexander KH, Minard G, et al. Accuracy of methods to estimate ionized and "corrected" serum calcium concentrations in critically ill multiple trauma patients receiving specialized nutrition support. JPEN J Parenter Enteral Nutr 2004;28:133-41. [Crossref] [PubMed]
7. Mateu-de Antonio J. New Predictive Equations for Serum Ionized Calcium in Hospitalized Patients. Med Princ Pract 2016;25:219-26. [Crossref] [PubMed]
8. Pekar JD, Grzych G, Durand G, et al. Calcium state estimation by total calcium: the evidence to end the never-ending story. Clin Chem Lab Med 2020;58:222-31. [Crossref] [PubMed]
9. Smith JD, Wilson S, Schneider HG. Misclassification of Calcium Status Based on Albumin-Adjusted Calcium: Studies in a Tertiary Hospital Setting. Clin Chem 2018;64:1713-22. [Crossref] [PubMed]
10. Besarab A, Caro JF. Increased absolute calcium binding to albumin in hypoalbuminaemia. J Clin Pathol 1981;34:1368-74. [Crossref] [PubMed]
11. Hamroun A, Pekar JD, Lionet A, et al. Ionized calcium: analytical challenges and clinical relevance. J Lab Precis Med 2020;5:22. [Crossref]
12. Yap E, Roche-Recinos A, Goldwasser P. Predicting Ionized Hypocalcemia in Critical Care: An Improved Method Based on the Anion Gap. J Appl Lab Med 2020;5:4-14. [Crossref] [PubMed]